scholarly journals Maturation of Monocyte-Derived DCs Leads to Increased Cellular Stiffness, Higher Membrane Fluidity, and Changed Lipid Composition

2020 ◽  
Vol 11 ◽  
Author(s):  
Jennifer J. Lühr ◽  
Nils Alex ◽  
Lukas Amon ◽  
Martin Kräter ◽  
Markéta Kubánková ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lymph Node ◽  
T Cell ◽  
T Cell Activation ◽  
Lipid Composition ◽  
Membrane Lipids ◽  
Building Blocks ◽  
Membrane Properties ◽  
Antigen Uptake ◽  
Peripheral Tissues

Dendritic cells (DCs) are professional antigen-presenting cells of the immune system. Upon sensing pathogenic material in their environment, DCs start to mature, which includes cellular processes, such as antigen uptake, processing and presentation, as well as upregulation of costimulatory molecules and cytokine secretion. During maturation, DCs detach from peripheral tissues, migrate to the nearest lymph node, and find their way into the correct position in the net of the lymph node microenvironment to meet and interact with the respective T cells. We hypothesize that the maturation of DCs is well prepared and optimized leading to processes that alter various cellular characteristics from mechanics and metabolism to membrane properties. Here, we investigated the mechanical properties of monocyte-derived dendritic cells (moDCs) using real-time deformability cytometry to measure cytoskeletal changes and found that mature moDCs were stiffer compared to immature moDCs. These cellular changes likely play an important role in the processes of cell migration and T cell activation. As lipids constitute the building blocks of the plasma membrane, which, during maturation, need to adapt to the environment for migration and DC-T cell interaction, we performed an unbiased high-throughput lipidomics screening to identify the lipidome of moDCs. These analyses revealed that the overall lipid composition was significantly changed during moDC maturation, even implying an increase of storage lipids and differences of the relative abundance of membrane lipids upon maturation. Further, metadata analyses demonstrated that lipid changes were associated with the serum low-density lipoprotein (LDL) and cholesterol levels in the blood of the donors. Finally, using lipid packing imaging we found that the membrane of mature moDCs revealed a higher fluidity compared to immature moDCs. This comprehensive and quantitative characterization of maturation associated changes in moDCs sets the stage for improving their use in clinical application.

scholarly journals Acquisition and presentation of follicular dendritic cell–bound antigen by lymph node–resident dendritic cells

2010 ◽  
Vol 208 (1) ◽  
pp. 135-148 ◽  
Author(s):  
Megan L. McCloskey ◽  
Maria A. Curotto de Lafaille ◽  
Michael C. Carroll ◽  
Adrian Erlebacher
Keyword(s):  
Dendritic Cells ◽  
Lymph Node ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Immune Complexes ◽  
Cell Activation ◽  
Follicular Dendritic Cell ◽  
Affinity Maturation ◽  
Follicular Dendritic

Follicular dendritic cells (DCs [FDCs]) are prominent stromal cell constituents of B cell follicles with the remarkable ability to retain complement-fixed antigens on their cell surface for extended periods of time. These retained immune complexes have long been known to provide the antigenic stimulus that drives antibody affinity maturation, but their role in cellular immunity has remained unclear. In this study, we show that FDC-retained antigens are continually sampled by lymph node–resident DCs for presentation to CD8 T cells. This novel pathway of antigen acquisition was detectable when FDCs were loaded with purified antigens bound into classical antigen–antibody immune complexes, as well as after pregnancy, when they are loaded physiologically with antigens associated with the complement-fixed microparticles released from the placenta into maternal blood. In both cases, ensuing antigen presentation was profoundly tolerogenic, as it induced T cell deletion even under inflammatory conditions. These results significantly broaden the scope of FDC function and suggest new ways that the complement system and persistent antigen presentation might influence T cell activation and the maintenance of peripheral immune tolerance.

scholarly journals PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Qi Peng ◽  
Xiangyan Qiu ◽  
Zihan Zhang ◽  
Silin Zhang ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Critical Role ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Tumor Control ◽  
Antigen Uptake

Abstract Immune checkpoint blockade therapies have shown clinical promise in a variety of cancers, but how tumor-infiltrating T cells are activated remains unclear. In this study, we explore the functions of PD-L1 on dendritic cells (DCs), which highly express PD-L1. We observe that PD-L1 on DC plays a critical role in limiting T cell responses. Type 1 conventional DCs are essential for PD-L1 blockade and they upregulate PD-L1 upon antigen uptake. Upregulation of PD-L1 on DC is mediated by type II interferon. While DCs are the major antigen presenting cells for cross-presenting tumor antigens to T cells, subsequent PD-L1 upregulation protects them from killing by cytotoxic T lymphocytes, yet dampens the antitumor responses. Blocking PD-L1 in established tumors promotes re-activation of tumor-infiltrating T cells for tumor control. Our study identifies a critical and dynamic role of PD-L1 on DC, which needs to be harnessed for better invigoration of antitumor immune responses.

scholarly journals Antigen-pulsed CD8α+ Dendritic Cells Generate an Immune Response after Subcutaneous Injection without Homing to the Draining Lymph Node

1999 ◽  
Vol 189 (3) ◽  
pp. 593-598 ◽  
Author(s):  
Adrian L. Smith ◽  
Barbara Fazekas de St. Groth
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Lymph Node ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Myeloid Dendritic Cells ◽  
Draining Lymph Node

Two subsets of murine splenic dendritic cells, derived from distinct precursors, can be distinguished by surface expression of CD8α homodimers. The functions of the two subsets remain controversial, although it has been suggested that the lymphoid-derived (CD8α+) subset induces tolerance, whereas the myeloid-derived (CD8α−) subset has been shown to prime naive T cells and to generate memory responses. To study their capacity to prime or tolerize naive CD4+ T cells in vivo, purified CD8α+ or CD8α− dendritic cells were injected subcutaneously into normal mice. In contrast to CD8α− dendritic cells, the CD8α+ fraction failed to traffic to the draining lymph node and did not generate responses to intravenous peptide. However, after in vitro pulsing with peptide, strong in vivo T cell responses to purified CD8α+ dendritic cells could be detected. Such responses may have been initiated via transfer of peptide–major histocompatibility complex complexes to migratory host CD8α− dendritic cells after injection. These data suggest that correlation of T helper cell type 1 (Th1) and Th2 priming with injection of CD8α+ and CD8α− dendritic cells, respectively, may not result from direct T cell activation by lymphoid versus myeloid dendritic cells, but rather from indirect modification of the response to immunogenic CD8α− dendritic cells by CD8α+ dendritic cells.

scholarly journals Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1354-1361 ◽  
Author(s):  
Elke Scandella ◽  
Ying Men ◽  
Silke Gillessen ◽  
Reinhold Förster ◽  
Marcus Groettrup
Keyword(s):  
Dendritic Cells ◽  
Lymph Node ◽  
T Cell ◽  
Prostaglandin E2 ◽  
Cyclic Adenosine Monophosphate ◽  
Human Monocyte ◽  
Adenosine Monophosphate ◽  
Cd40 Ligand ◽  
Soluble Cd40 Ligand ◽  
Peripheral Tissues

Dendritic cells (DCs) are potent antigen-presenting cells that are able to initiate and modulate immune responses and are hence exploited as cellular vaccines for immunotherapy. Their capacity to migrate from peripheral tissues to the T-cell areas of draining lymph nodes is crucial for the priming of T lymphocytes. In this study, we investigated how the maturation of human monocyte-derived DCs (MoDCs) by several different stimuli under serum-free conditions affected their T-cell stimulatory function, cytokine secretion, and migratory behavior. Surprisingly, we found that for all maturation stimuli tested, the addition of prostaglandin E2 (PGE2) was required for effective migration of MoDCs toward the lymph node–derived chemokines CCL19 (EBI1 ligand chemokine/macrophage inflammatory protein–-3β) and CCL21 (secondary lymphoid tissue chemokine [SLC]/6Ckine). Costimulation with PGE2 enhanced the expression of the CCL19/CCL21 receptor CCR7 on the cell surface of MoDCs when they were matured with soluble CD40 ligand or proinflammatory cytokines, but did not affect CCR7 expression of polyI:C–stimulated MoDCs. The effects of PGE2 on MoDCs were mediated through increased cyclic adenosine monophosphate by 2 of the known PGE2 receptors, EP2 and EP4, which are expressed and down-regulated after PGE2 binding in these cells. In conclusion, our results suggest that signals provided by the proinflammatory mediator PGE2 are crucial for MoDCs to acquire potent T-helper cell stimulatory capacity and substantial chemotactic responsiveness to lymph node–derived chemokines. This is a new and important parameter for the preparation of MoDCs as cellular vaccines in tumor immunotherapy.

scholarly journals Neonatal lymph node stromal cells drive myelodendritic lineage cells into a distinct population of CX3CR1+CD11b+F4/80+ regulatory macrophages in mice

Blood ◽  
2012 ◽  
Vol 119 (17) ◽  
pp. 3975-3986 ◽  
Author(s):  
Xiangyue Zhang ◽  
Songfeng Yu ◽  
Katharina Hoffmann ◽  
Kai Yu ◽  
Reinhold Förster
Keyword(s):  
Dendritic Cells ◽  
Lymph Node ◽  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Stromal Cells ◽  
Cell Activation ◽  
Distinct Population ◽  
Lymph Node Stromal Cells

Abstract Beyond providing a scaffold for immune cells, recent studies indicate that lymph node stromal cells provide potent regulatory capacities that affect the quality of adaptive immune responses. In this study, we provide evidence that neonatal lymph node stromal cells (nnLNSCs) consistently promote the differentiation of macrophage dendritic cell progenitors as well as mature and immature dendritic cells into a distinct population of CX3CR1+ CD11b+F4/80+ regulatory macrophages (regMΦ). These cells possess remarkably low levels of T cell costimulatory molecules as well as MHC class II molecules. regMΦ do not interfere with early T-cell activation but, via nitric oxide secretion, efficiently suppress T-cell proliferation. Furthermore, CD4+ T cells proliferating in the presence of regMΦ gain immunosuppressive capacity and MΦ isolated from day 3 nnLNs are T-cell immunosuppressive. Adoptive transfer of antigen-loaded regMΦ induce a profound antigen-specific immune suppression in vivo. Together our data show that nnLNSCs skew the differentiation of dendritic cells and their progenitors toward regMΦ, thus revealing a novel mechanism for local immune regulation.

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